Sulphoxides

ABSTRACT

The compounds are sulphoxides of heterocyclicthioalkylthioureas, ureas and guanidines which are useful to produce inhibition of histamine H-2 receptors.

This is a division of application Ser. No. 627,418 filed Oct. 30, 1975,now U.S. Pat. No. 3,979,398, which is a division of application Ser. No.436,285 filed Jan. 24, 1974, now U.S. Pat. No. 3,932,443.

This invention relates to sulphoxides, to processes for theirpreparation and to pharmaceutical compositions comprising them. Thesulphoxides of the invention can exist as the addition salt with an acidbut, for convenience reference will be made throughout thisspecification to the parent compounds.

Histamine H-2 receptor antagonists have been defined by Black et al.(Nature 1972, 236, 385) as those compounds which inhibit certain actionsof histamine which are not inhibited by the class of substances such asmapyramines which have been commonly called "antihistamines" and whichmay now be referred to as histamine H-1 receptor antagonists.

Our U.K. Specification No. 1,338,169 describes, inter alia, thioethercompounds which are useful as histamine H-2 receptor antagonists and itis with the sulphoxides of certain of these compounds that the presentinvention is concerned.

According to the present invention we provide sulphoxides of thefollowinging structural formula I: ##STR1## wherein A is such that thereis formed with the carbon atom shown an unsaturated heterocyclicnucleus, preferably having five or six atoms, which nucleus comprises atleast one nitrogen atom and may comprise further hereto atoms such assulphur and oxygen e.g. imidazole, pyridine, thiazole, isothiazole,oxazole, isoxazole, pyrazole, triazole, thiadiazole, pyrimidine,pyrazine or pyridazine; X₁ and X₂ which may be the same or different arehydrogen, lower alkyl, trifluoromethyl, hydroxyl, halogen, amino, or X₁may with X₂ and at least two of the atoms comprising A form a furtherring e.g. a benzene ring, a pyrimidine rng or a partially unsaturatedring; K is 0 to 2 and m is 2 or 3 provided that the sum of k and m is 3or 4; E is oxygen, sulphur or NR₂ ; R₁ is hydrogen, lower alkyl such asmethyl, acyl e.g. benzoyl or dialkylaminoalkyl e.g. dimethylaminoethyl;and R₂ is hydrogen, nitro, cyano, alkanesulphonyl or arenesulphonyl.

Preferably A is such that it forms with the carbon atom shown animidazole, thiazole or pyridine ring. Preferably X₁ is hydrogen, methyl,bromine, amino or hydroxyl and X₂ is hydrogen. Preferably k is from 1 to2 and m is 2 or 3 and particularly useful compounds are those wherein kis 1 and m is 2. Preferably E is sulphur or NR₂ wherein R₂ is cyano.Preferably R₁ is methyl.

Particularly useful compounds which are within the scope of the presentinvention are (5-methyl-4-imidazolyl)methyl 2-(N'-methylthioureido)ethyl sulphoxide andN-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylsulphinyl)ethyl]guanidine.

The compounds of the present invention may be prepared from amines ofthe following formula II: ##STR2## wherein A, X₁, X₂, k and m have thesame significance as in the substance of formula I, by treatment with anoxidising agent such as perbenzoic or peracetic acid or, preferably,with periodate e.g. sodium periodate. This results in the production ofa compound of formula III ##STR3## wherein A, X₁, X₂, k and m have thesame significance as in the substance of formula I, which may beisolated or which may be further reacted, without isolation, with anappropriate reactant to yield the required compound of formula I.

The compounds of Formula I where R₁ is lower alkyl and E is sulphur maybe prepared from the amine of Formula III by reaction with anisothiocyanic ester of Formula R₁ --N═C═S in an appropriate solvent suchas chloroform, ethanol, isopropanol, acetonitrile or water

Compounds of Formula I wherein E is oxygen may be formed from the amineof Formula III by treatment thereof with an isocyanate of Formula R₁ NCOwherein R₁ is lower alkyl. The compounds of Formula I wherein E isoxygen and R₁ is hydrogen may be obtained by reaction of the said amineswith sodium or potassium cyanate.

Compounds of Formula I wherein E is NR₂ may be prepared from the amineof Formula III by treatment thereof with an isothiourea of Formula IV.##STR4## wherein R₁ has the same significance as in Formula I.

In the case where R₂ is cyano, the amine of formula III may be treatedwith a dialkyldithiocyanimidocarbonate or dialkylcyanimidocarbonate offormula V

    (r.sub.3 y).sub.2 c═n-cn                               formula v

wherein R₃ is lower alkyl, preferably methyl and Y is sulphur or oxygen,preferably sulphur to yield a compound of formula VI ##STR5## wherein A,X₁, X₂, k and m have the same significance as in formula I and R₃ and Yhave the same significance as in formula V. Treatment of the substanceof formula VI with an amine of formula R₁ NH₂ wherein R₁ is hydrogen,lower alkyl or aralkyl yields the required compound of formula I.

The amines of Formula II may be produced by the processes described inour U.K. Specification No. 1,338,169 namely from a substance of FormulaVII ##STR6## wherein A, X₁, X₂ and k have the same significance as inthe substance of Formula I; and Q is hydroxyl, halogen or methoxy. Inthe first stage of these processes, the compound of Formula VII isreacted with an amino-mercaptan of the following Formula VIII

    hs -- (ch.sub.2).sub.m NH .sub.2

formula

                                                               VIII

wherein m has the same significance as in Formula I. When Q is halogen,this reaction may be carried out under strongly basic conditions, forexample in the presence of sodium ethoxide or sodium hydroxide. Sincethe substance of Formula VII is a primary amine, it may be necessary toprotect the amino group, for example by a phthalmido group which maysubsequently be removed by acid hydrolysis or hydrazinolysis. When Q ishydroxyl or halogen it is found that the reaction will take place underacidic conditions e.g. in the presence of a halogen acid such as 48%aqueous hydrogen bromide, or a halogen acid in the presence of glacialacetic acid. When Q is methoxy, the reaction will also take place in thepresence of 48% hydrogen bromide.

In an alternative method for the production of our sulphoxide compounds,which is particularly suitable when E is oxygen or N-cyano, thecorresponding thioether compound of formula IX: ##STR7## wherein A, X₁,X₂, k, m and R₁ have the same significance as in Formula I and E¹ isoxygen or N-cyano, is treated with an oxidising agent such as perbenzoicor peracetic acid or, preferably, with periodate e.g. sodium periodate.The reaction may conveniently be carried out in a suitable solvent e.g.water.

It will be appreciated that whichever of the above methods is used, anessential step in the process is the treatment of a thioether compoundof formula X. ##STR8## wherein A, X₁, X₂, k and m have the samesignificance as in Formula I and Q is hydrogen or ##STR9## wherein E andR₁ have the same significance as in Formula I, with an oxidising agentof the type mentioned hereinbefore.

The sulphoxides of the present invention find their utility in theinhibition of histamine H-2 receptors in the animal body. Although we donot wish to be limited in any way by the following explanation of thisutility, we believe that this is largely due to the metabolic reductiveconversion of the sulphoxides to the corresponding thioether compoundswhich are of course, as stated above, highly effective as histamine H-2receptor antagonists. This conversion is thought to occur in the largeintestine of the animal where the active reducing agent is probablypresent in the intestinal bacterial flora. Because of this mechanism theprinciple H-2 antagonism action may be delayed for some considerabletime after the administration to the animal of the sulphoxides. This isa particularly useful effect in many cases and may be utilised, forexample to provide a continuing supply of antagonist to the animal afterthe effects of an initial does e.g., of a compound of the type describedin U.K. Specification No. 1,338,169 has started to decline. In thisregard it is of course possible to administer the sulphoxides of thepresent invention at the same time and possibly in combination with thesaid initial dose.

In support of the above explanation of the histamine H-2 receptorinhibition resulting from the administration to animals of thesulphoxides according to the present invention it has been shown that,after oral administration of the sulphoxide, for example to rats at 300mg/kg orally, the corresponding thioether reduction product can bedetected in body fluids e.g., urine and furthermore that incubation ofthe sulphoxide with rat, dog or human faecal homogenates results insubstantial reduction to the corresponding thioether. Thus, thecompounds of this invention produce histamine H-2 receptor inhibition inrats at the dose stated above. Inhibitors of histamine H-2 receptors areuseful, for example, as inhibitors of gastric acid secretion.

In addition to the above, certain of the sulphoxides of the presentinvention show activity as histamine H-2 receptor antagonists on thevarious tests which, as described by Black et. al. (Nature 1972, 236,387), characterise this activity. For example, they inhibit thehistamine stimulated increase in the contraction frequency of isolatedguinea pig atrium in oxygenated McEwen's solution at 34° C. As explainedby Black et. al (Nature, 1972, 236, 387) this effect can be quantifiedin terms of the displacement of the dose-response curves wherein the logof the molar concentration of histamine required to produce a responseup to a maximum is plotted against the response (expressed as apercentage of the maximum). When competitive antagonism occurs, a seriesof parallel sigmoid curves are obtained corresponding to differentconcentrations of antagonist and, from these data, the apparentdissociation constant (K_(B)) for the antagonist-receptor interactioncan be calculated. Certain of the sulphoxides of Formula I exhibit thetypical characteristics of a competitive antagonist in this test, forexample (5-methyl-4-imidazolyl)methyl 2-(N¹ -methylthioureido)sulphoxide which has a K_(B) of the order of 10 micromolar.

The compounds of Formula I may be combined with a pharmaceuticallyacceptable carrier to form pharmaceutical compositions. Advantageouslythe compositions will be made up in an appropriate dosage form. Thepharmaceutical carrier employed may be, for example, either a solid orliquid. Exemplary of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acidand the like. Exemplary of liquid carriers are syrup, peanut oil, oliveoil, water and the like. Other pharmacologically active compounds may incertain cases be included in the pharmaceutical compositions, forexample as mentioned above, a thioether compound which may or may not beexact analogue of the sulphoxide, may be included.

A wide variety of pharmaceutical forms can be employed; thus if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form, or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg to about 1 gm. If a liquid carrier is used, thepreparation may be in the form of a syrup, emulsion, soft gelatincapsule, or an aqueous or nonaqueous liquid suspension. Thepharmaceutical compositions are prepared by conventional techniquesinvolving procedures such as mixing, granulating and compressing ordissolving the ingredients as appropriate to the desired preparation.

The active ingredient will be present in the composition in an amountsuch that effective inhibition of H-2 histamine receptors is eventuallyachieved. The route of administration should be such that the sulphoxidecan eventually reach the large intestine and is thus preferably orally.

For therapeutic use, the compounds of the present invention willnormally be administered as a pharmaceutical composition comprising asthe or an essential active ingredient at least one such compound in thebasic form or in the form of an addition salt with a pharmaceuticallyacceptable acid and in association with a pharmaceutical carriertherefor. Such addition salts include those with hydrochloric,hydrobromic, hydriodic, sulphuric, picric and maleic acids and theaddition salt with one of these acids may readily be converted to thatwith another. Such conversion may be effected by means of ion-exchangetechniques. A particularly useful method which also in many caseseffects purification to a sufficient degree to allow the resultantsolution of the addition salt to be used for pharmacological estimationsinvolves the formation of the picrate salt and conversion therefrom tothe chloride salt.

The invention is illustrated but in no way limited by the followingexamples:

EXAMPLE 1 Preparation of (5-Methylimidazol-4-yl)methyl2-(N'-methylthioureido)ethyl sulphoxide

i. A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30 g)and cysteamine hydrochloride (23 g) in acetic acid (200 ml) was heatedunder reflux for 10 hours. Following cooling to 15°-20° C, the solidwhich crystallised was collected and washed with isopropyl alcohol togive 2[(5-methylimidazol-4-yl)methyl]thioethylamine dihydrochloride(45.5 g), m.p. 189°-192° C.

ii. 2[5-Methylimidazol-4-yl)methyl]thioethylamine dihydrochloride (14.5g, 0.06 ml) was added in two portions to a stirred solution of sodiummetaperiodate (13.5 g, 0.063 mol) in water (126 ml) kept at 2°-5° C,stirred at this temperature for 3 hours and then left overnight at 0° C.The solid was filtered off and washed with methanol and the combinedfiltrate and washings (which had deposited more solid which was filteredagain) were basified to pH 9.10 by addition of potassium carbonate (15g) and evaporated to dryness under reduced pressure at 70° withazeotroping with n-propanol. Extraction of the residue with isopropanoland evaporation of the filtered extracts gave crude(5-methylimidazol-4-yl)methyl 2-aminoethyl sulphoxide as an oil. (Theinfra red spectrum indicated SO absorption at 1020, 1040 cm⁻¹).

iii. This oil was dissolved in ethanol (250 ml) containing 3 drops waterand methyl isothiocyanate (5.1 g, 0.07 mol) was added. The solution wasleft at room temperature overnight, by which time thin-layerchromatography (silica-gel plate; ethyl acetate/methanol/ammoniumhydroxide (5:1:1); visualised by UV and potassium iodoplatinate)indicated complete disappearance of amine, and product formed (whitespot K.I.P. initially mauve). Purification by chromatography on silicagel and crystallisation in acetonitrile gave, after finalcrystallisation from methanolether,(5-Methylimidazol-4-yl)methyl-2(N'-methylthioureido)ethyl sulphoxide(7.1 g,) m.p. 135°-7° C. An analytical sample after a furtherrecrystallisation had m.p. 139°-140° C. Found: C,41.39; H, 6.35; N,21.39 C₉ H₁₆ N₄ OS₂ requires: C, 41.51; H, 6.19; N, 21.52;

EXAMPLE 2 Preparation ofN-Cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylsulphinyl)ethyl]guanidine

Sodium metaperiodate (1.85 g, 8.68 m.mol.) was added to a stirred,cooled (5°) solution ofN-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine(2.085 g, 8.27 m.mol.) in water (83 ml). After 90 minutes stirring at 5°thin layer chromatography indicated almost complete disappearance ofstarting material. The solution was allowed to stand overnight at roomtemperature to complete the reaction, then evaporated under reducedpressure to dryness, with azeotroping with n-propanol. The residue wasboiled with isopropanol (60 ml), filtered hot, and the filtrate wasevaporated to dryness to give the crude product as a glass. This waspurified by charcoaling in methanol (40 ml), filtration and dilutionwith ether to 1500 ml. The liquid was decanted from the flocculentprecipitated glass which was kept under a further 1500 ml ether tobecome semicrystalline, then filtered and allowed to stand overnight inair. The hardened glass was stirred with cold methanol (25 ml) filteredfrom insoluble crude product and and inorganics (0.28 g. m.p. 190°) andto the filtrate was carefully added ether (to 500 ml) so that two layersformed. On standing undisturbed for 3 days there separated off whitecrystals ofN-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylsulphinyl)ethyl]guanidine(1.55 g), m.p. 185°-186.5° C. Found: C,44.57; H,6.08; N, 31.18; S,11.91%C₁₀ H₁₆ N₆ OS requires C, 44.76; H, 6.01; N,31.32; S,11.95%.

EXAMPLE 3 Preparation ofN-Cyano-N'-methyl-N"-[2-((2-thiazolyl)methylsulphinyl)ethyl]guanidine.

Sodium metaperiodate (220 mg, 1.03 m.mol) was added to a stirredsolution of N-cyano-N'-methyl-N"-[2-((2-thiazolyl)methylthio)ethyl]guanidine (255 mg, 1.0 m.mol) in water (90 ml). After 1hour at 25° then 17 hours at 5° t.l.c. indicated the reaction wasessentially complete. The solution was evaporated under reduced pressureat 60° to dryness, with azeotroping with n-propanol (2x). The residuewas boiled with isopropanol (20 ml) for 3 minutes, filtered hot from 205mg of inorganic salts, (100%), and evaporated under reduced pressure toa clear glass which was stirred continuously for 4 days under ether togive crude product (273 mg, 100%) m.p. 110° (softens only). Purificationwas effected by dissolution in acetonitrite (15 ml) and dilution of thefiltered warm solution with ether to 220 ml. After 17 hours standing theprecipitate had crystallised yielding, after filtration and washing withether, N-cyano-N'-methyl-N"-[2-((2-thiazolyl)methylsulphinyl)ethyl]guanidine, (335 mg), m.p.112°-113° C. Found: C, 39.62; H, 5.03; N, 25.64%. C₉ H₁₃ N₅ OS₂requires: C, 39.83; H, 4.83; N, 25.81%.

EXAMPLE 4

Treatment of (5-methylimidazol-4-yl)methyl 2-aminoethyl sulphoxideaccording to the method of Example 1 (iii) with the following compounds:

a. ethyl isothiocyanate

b. 2-(dimethylamino)ethyl isothiocyanate

c. S-methylisothiourea

d. S-methyl-N-nitroisothiourea

e. benzoyl isothiocyanate

yielded the following compounds:

a. (5-methylimidazol-4-yl)methyl 2-(N'-ethylthioureido)ethyl sulphoxide

b. (5-methylimidazol-4-yl)methyl 2-[N'-2-(dimethylamino)ethylureido]ethyl sulphoxide

c. (5-methylimidazol-4-yl)methyl 2-guanidinoethyl sulphoxide)

d. (5-methylimidazol-4-yl)methyl 2-(N'-nitroguanidino)ethyl sulphoxide

e. (5-methylimidazol-4-yl)methyl 2-(N'-benzoylthioureido)ethylsulphoxide

Alkaline hydrolysis with aqueous potassium carbonate of the lastmentioned sulphoxide yielded

f. (5-methylimidazol-4-yl)methyl 2-thioureidoethyl sulphoxide.

EXAMPLE 5

By subjecting the following amino compounds to the reactions describedin Example 1 (ii) and 1 (iii):

a. 2-[(imidazol-4-yl)methyl]thioethylamine

b. 2-[(5-ethylimidazol-4-yl)methyl]thioethylamine

c. 2-[(5-isopropylimidazol-4-yl)methyl]thioethylamine

d. 2-[(5-benzylimidazol-4-yl)methyl]thioethylamine

e. 2-[(5-bromoimidazol-4-yl)methyl]thioethylamine

f. 2-[(2-methylimidazol-4-yl)methyl]thioethylamine

g. 2-[(imidazol-2-yl)methyl]thioethylamine

h. 2-[(1,5-dimethylimidazol-2-yl)methyl]thioethylamine

i. 2-[(1-methyl-5-chloroimidazol-2-yl)methyl]thioethylamine

j. 2-[(3-1,2,4 triazol-3-yl)methyl]thioethylamine

k. 2-[(pyrazol-3-yl)methyl]thioethylamine

l. 2-[(pyrid-2-yl)methyl]thioethylamine

m. 2-[(3-hydroxypyrid-2-yl)methyl]thioethylamine

n. 2-[(pyridazin-3-yl)methyl]thioethylamine

o. 2-[(5-amino-1,3,4-thiadiazol-2-yl)methyl]thioethylamine

p. 2-[(5-trifluoromethylimidazol-4-yl)methyl]thioethylamine

q. 2-[(pyrimidin-2-yl)methyl]thioethylamine

r. 2-[(pyrazin-2-yl)methyl]thioethylamine

s. 2-[(2-aminothiazol-3-yl)methyl]thioethylamine

t. 2-[(isothiazol-3-yl)methyl]thioethylamine

u. 2-[(4-bromoisothiazol-3-yl)methyl ]thioethylamine

v. 2-[(3-aminopyrid-2-yl)methyl]thioethylamine

w. 3-[(imidazol-4-yl)methyl]thiopropylamine

x. 2-[2-(imidazol-4-yl)ethyl]thioethylamine

y. 2-[(benzimidazol-2-yl)methyl]thioethylamine

the following sulphoxides may be produced:

a. (imidazol-4-yl)methyl 2-(N'-methylthioureido)ethyl sulphoxide

b. (5-ethylimidazol-4-yl)methyl 2-(N'-methylthioureido)ethyl sulphoxide

c. (5-isopropylimidazol-4-yl)methyl 2-(N'-methylthioureido)ethylsulphoxide

d. (5-benzylimidazol-4-yl)methyl 2-(N'-methylthioureido)ethyl sulphoxide

e. (5-bromoimidazol-4-yl)methyl 2-(N'-methylthioureido)ethyl sulphoxide

f. (2-methylimidazol-4-yl)methyl 2-(N'methylthioureido)ethyl sulphoxide

g. (imidazol-2-yl)methyl 2-(N'-methylthioureido)ethyl sulphoxide

h. (1,5-dimethylimidazol-2-yl)methyl 2-(N'-methylthioureido)ethylsulphoxide

i. (1-methyl -5-chloroimidazol-2-yl)methyl 2-(N'-methylthioureido)ethylsulphoxide

j. (3-1,2,4 triazol-3-yl)methyl 2-(N'-methylthioureido)ethyl sulphoxide

k. (pyrazol-3-yl)methyl 2-(N'-methylthioureido)ethyl sulphoxide

l. (pyrid-2-yl)methyl 2-(N'-methylthioureido)ethyl sulphoxide

m. (3-hydroxypyrid-2-yl)methyl 2-(N'-methylthioureido)ethyl sulphoxide

n. (pyridazin-3-yl)methyl 2-(N'-methylthioureido)ethyl sulphoxide

o. (5-amino-1,3,4-thiadiazol-2-yl)methyl 2-(N'-methylthioureido)ethylsulphoxide

p. (5-trifluoromethylimidazol-4-yl)methyl 2-(N'-methylthioureido)ethylsulphoxide

q. (pyrimidin-2-yl)methyl 2-(N'-methylthioureido)ethyl sulphoxide

r. (pyrazin-2-yl)methyl 2-(N'-methylthioureido)ethyl sulphoxide

s. (2-aminothiazol-3-yl)methyl 2-(N'-methylthioureido)ethyl sulphoxide

t. (isothiazol-3-yl)methyl 2-(N'-methylthioureido)ethyl sulphoxide

u. (4-bromoisothiazol-3-yl)methyl 2-(N'-methylthioureido)ethylsulphoxide

v. (3-aminopyrid-2-yl)methyl 2-(N'-methylthioureido)ethyl sulphoxide

w. (imidazol-4-yl)methyl 3-(N'-methylthioureido)propyl sulphoxide

x. 2-imidazol-4-yl)ethyl 2-(N'-methylthioureido)ethyl sulphoxide

y. (benzimidazol-2-yl)methyl 2-(N'-methylthioureido)ethyl sulphoxide clEXAMPLE 6

Periodate oxidation of the following compounds by the proceduredescribed in EXAMPLE 2.

a.N-cyano-N'-ethyl-N"-[2-((4-methyl-5-imidazoyl)methylthio)ethyl]guanidine

b.N-cyano-N'-methyl-N"-[2-((3-hydroxy-2-pyridyl)methylthio)ethyl]guanidine

c.N-cyano-N'-methyl-N"-[2-((4-bromo-5-imidazolyl)methylthio)ethyl]guanidine

d.N-cyano-N'-methyl-N"-[3-((4-methyl-5-imidazolyl)methylthio)propyl]guanidine

e. N-cyano-N'-methyl-N"-[2-((3-isothiazolyl)methylthio)ethyl]guanidine

f.N-cyano-N'-methyl-N"-[2-((3-bromo-2-pyridyl)methylthio)ethyl]guanidine

g. N-methyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]urea.

h. N-methyl-N'-[2-((2-pyridyl)methylthio)ethyl]urea

led to the production of the following compounds:

a. N-cyano-N'-ethylN"-[2-((4-methyl-5-imidazolyl)methylsulphinyl)ethyl]guanidine

b.N-cyano-N'-methyl-N"-[2-((3-hydroxy-2-pyridyl)methylsulphinyl)ethyl]guanidine

c.N-cyano-N'-methyl-N"-[2-((4-bromo-5-imidazolyl)methylsulphinyl)ethyl]guanidine

d.N-cyano-N'-methyl-N"-[3-((4-methyl-5-imidazolyl)methylsulphinyl)propyl]guanidine

e.N-cyano-N'-methyl-N"-[2-((3-isothiazolyl)methylsulphinyl)ethyl]guanidine

f.N-cyano-N'-methyl-N"-[2-((3-bromo-2-pyridyl)methylsulphinyl)ethyl]guanidine

g. N-methyl-N'-[2-((4-methyl-5-imidazolyl)methylsulphinyl)ethyl]urea

h. N-methyl-N'-[2-((2-pyridyl)methylsulphinyl)ethyl]urea

EXAMPLE 7

Treatment of (5-methylimidazol-4-yl)methyl 2-aminoethyl sulphoxide underreflux conditions in acetonitrile with the following isothioureas:

a. N-benzenesulphonyl-S-methylisothiourea

b. N-(4-chlorobenzenesulphonyl)-S-methylisothiourea

c. N-methanesulphonyl-S-methylisothiourea

d. N-n-propanesulphonyl-S-methylisothiourea

e. N-p-toluenesulphonyl-S-methylisothiourea

and isolation and recrystallisation of the product yielded:

a. N-benzenesulphonyl-N'-methyl-N"-2-((4-methyl-5-imidazolyl)methylsulphinyl)ethyl guanidine

b. N-(4-chlorobenzenesulphonyl)-N'-methyl-N"-2-((4-methyl-5-imidazolyl)methylsulphinyl)ethyl guanidine

c. N-methanesulphonyl-N'-methyl-N"-2-((4-methyl-5-imidazolyl)methylsulphinyl)ethyl guanidine

d. N-n-propanesulphonyl-N'-methyl-N"-2-((4-methyl-5-imidazolyl)methylsulphinyl)ethyl guanidine

e. N-p-toluenesulphonyl-N'-methyl-N"-2-((4-methyl-5-imidazolyl)methylsulphinyl)ethyl guanidine

EXAMPLE 8

    ______________________________________                                        Ingredients            Amounts                                                ______________________________________                                        (5-Methylimidazol-4-yl)methyl                                                 2-(N'-methylthioureido)ethyl sulphoxide                                                              150 mg                                                 Sucrose                75 mg                                                  Starch                 25 mg                                                  Talc                   5 mg                                                   Stearic Acid           2 mg                                                   ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

EXAMPLE 9

    ______________________________________                                        N-Cyano-N'-methyl-N"-[2-((4-methyl-                                           5-imidazolyl)methylsulphinyl)ethyl]guanidine                                                             200 mg                                             Lactose                    100 mg                                             ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

What we claim is:
 1. A compound of the formula: ##STR10## wherein A issuch that the heterocyclic nucleus formed is a thiazole or oxazole ring;X₁ and X₂, which may be the same or different are hydrogen, lower alkyl,trifluoromethyl, halogen or amino k is 0 to 2 and m is 2 or 3 providedthat the sum of k and m is 3 or 4; E is oxygen, sulphur or NH₂ ; R₁ ishydrogen, lower alkyl, benzoyl or dimethylaminoethyl; and R₂ ishydrogen, nitro, cyano, alkanesulphonyl having 1 to 3 carbon atoms,benzenesulphonyl, halobenzenesulphonyl or toluenesulphonyl.
 2. Acompound of claim 1 wherein A is such that the heterocyclic nucleusformed is a thiazole ring.
 3. A compound of claim 1 wherein X₁ ishydrogen, methyl, bromine or amino and X₂ is hydrogen.
 4. A compound ofclaim 1 wherein k is 1 or 2 and m is 2 or
 3. 5. A compound of claim 4wherein k is 1 and m is
 2. 6. A compound of claim 1 wherein E is sulphuror NR₂ wherein R₂ is cyano.
 7. A compound of claim 1 wherein R₁ ismethyl.
 8. A compound of claim 1, said compound beingN-cyano-N'-methyl-N"-[2-((2-thiazolyl)methylsulphinyl)ethyl]guanidine.9. A compound of claim 1, said compound being(2-aminothiazol-3-yl)methyl 2-(N'-methylthioureido)ethyl sulphoxide. 10.A pharmaceutical composition to inhibit histamine H-2 receptorscomprising in an amount effective to inhibit said receptors a compoundof claim 1 together with a pharmaceutically acceptable diluent orcarrier.